MX2007005207A - Dye-free pharmaceutical suspensions and related methods. - Google Patents

Abstract

A dye-free pharmaceutical suspension having a therapeutically effective amount of a first active agent consisting essentially of a first substantially water insoluble active agent, an effective amount of non-reducing sweetener; an effective amount of water; and an effective amount of a suspending system; wherein the dye-free pharmaceutical suspension has a pH of from about 5 to about 6 and is substantially free of a reducing sugar and related methods.

Description

PHARMACEUTICAL SUSPENSIONS WITHOUT COLORING AND RELATED METHODS FIELD OF THE INVENTION This invention relates to pharmaceutical compositions. More particularly, the invention relates to pharmaceutical suspensions without dye containing at least one active agent substantially insoluble in water, for example paracetamol.

BACKGROUND OF THE INVENTION Medicaments or pharmaceuticals administered orally are given to the patient in many forms, including solid forms such as capsules, caplets, gelcaps or tablets, and liquid forms as solutions, for example syrups and elixirs, emulsions or suspensions. Normally, medications administered in solid form are intended to be whole swallowed; therefore, to formulate the medicament it is not necessary to take into account the often unpleasant taste of the active agent, except for the provision of means to prevent the taste from being evident during the short time that the medicament is in the mouth. Such means may include the provision of an appropriately thin and rapidly soluble coating on a tablet or caplet, or use a gelatin capsule shape (the outer gelatin shell of the capsule keeps the active agent inside until the capsule has been swallowed), or simply compressing a tablet firmly so that it does not begin to disintegrate during the short time that is destined to be in the mouth. Children, the elderly, and many others, including disabled or disabled patients, have trouble swallowing solid forms, such as whole tablets and even capsules. Therefore, in cases where the dose to be administered can not be made in a very small tablet or capsule, it is desirable to provide the medicament in a chewable solid form or in a liquid form. For many patients, including pediatric and geriatric patients, a liquid oral dosage form over the chewable dosage form is preferable, due to the rapid swallowing without chewing of the liquid dosage form. A common problem associated with liquid dosage forms is the often unpleasant taste of the active agents, which manifests itself during the time that the liquid dosage form is in the mouth before swallowing. Although suspensions typically offer a taste masking superior to other liquid forms, those skilled in the art are aware of the considerable technical difficulties in producing a stable and organoleptically acceptable suspension. The suspensions are a two-phase system having particles of a solid active agent substantially insoluble in water, dispersed throughout the liquid medium. A suspension does not cover emulsions, which describes liquids suspended in liquid carriers or syrup formulations containing only fully dissolved pharmaceutical active agents. As used herein, a "particle" can be a crystal, a granule, an agglomerate, or any solid material not dissolved. The particles of the present invention preferably have a mean particle size (d50%) of about 150 microns, preferably from about 10 microns to about 100 microns. Previously problems have been handled to keep the active agent substantially insoluble in water suspended, ensuring the stability of the active agent substantially insoluble in water, and maintaining the uniformity of the doses over a prolonged period. See, for example, U.S. Pat. UU Nos. 5,409,907 and 5,374,659. In a pharmaceutical suspension, at least one active agent is usually present substantially in the form of undissolved solid particles, ie, the active agent substantially insoluble in water. However, in any of these systems, a portion of said active agent may be in the dissolved state. In formulating such systems, it is advantageous to minimize the amount of drug present in the dissolved state. The minimization of the amount of the active agent in solution is advantageous both for the taste and for the chemical and physical stability of the product. Dyes are often added to the pharmaceutical suspensions to give them elegance and to mask the discoloration. Without However, it has been found that some patients develop or have allergies to, or are sensitive to, suspensions with dye, or that such suspensions stain clothing, furniture, rugs and the like when spilled. Therefore, suspensions without dye are very desirable. Coloring agents are frequently added to liquid pharmaceuticals to produce pharmaceutically acceptable characteristics, to provide an identification factor and also to provide consistency between batches of a product. Many times the color of the excipients that are used to manufacture the product contributes to a discoloration of the product. This color generally depends on the batches of the excipients and can change during storage without adverse effects on the product. However, the consumer perceives the change in color as an adverse effect on the effectiveness of the product, resulting in the rejection of the product. The stability of paracetamol (N-acetyl-para-aminophenol or "APAP") is affected by the excipients of the formulation that are necessary to manufacture an acceptable product. In this way, there are many manufacturing problems of an acceptable APAP liquid product, without colorant. When preparing an APAP product in suspension, the formulator must ensure that the sensory properties are acceptable and the product is acceptable to the user. In this respect, flavorings are added to the product, sweeteners and consistency modifiers required. In addition, the formulator must also know the necessary pharmaceutical attributes that must be incorporated into the product. These include: acceptable suspension and stability properties and acceptable microbial properties. All these requirements complicate the challenge of manufacturing an acceptable APAP product in suspension, without colorant. The present invention is directed to the discovery of a suspension system of aqueous APAP without colorant, stable, which achieves an acceptable dosage form for geriatric applications and, especially, pediatric applications.

BRIEF DESCRIPTION OF THE INVENTION As fully incorporated and described herein, the present invention provides a pharmaceutical suspension without dye comprising, consisting, and / or consisting essentially of: (a) a therapeutically effective amount of a first active agent consisting essentially of a first active agent substantially insoluble in water; (b) an effective amount of a non-reducing sweetener; (c) an effective amount of water; and (d) an effective amount of a suspension system; wherein the pharmaceutical suspension without dye has a pH of about 5 to about 6, and is substantially free of a reducing sugar. Another embodiment of the present invention includes a suspension of APAP without colorant, comprising, consisting, and / or consisting essentially of: (a) a therapeutically effective amount of APAP; (b) an effective amount of a non-reducing sweetener; (c) an effective amount of water; and (d) an effective amount of a suspension system; wherein the pharmaceutical suspension without dye has a pH of about 5 to about 6, and is substantially free of a reducing sugar. A further embodiment of the present invention includes an APAP suspension without colorant, comprising, consisting, and / or consisting essentially, for each 100 mL of said suspension, in: from about 1 g to about 15 g of APAP; from about 0.1 g to about 0.25 g of xanthan gum; from about 0.4 g to about 1 g of microcrystalline cellulose; from about 20 g to about 65 g of sorbitol solution; from about 1 g to about 20 g of glycerin; from about 0.01 g to about 1 g of flavor; from about 20 g to about 50 g of water; from about 0.001 g to about 0.10 g of an antimicrobial preservative selected from the group consisting of butylparaben, methylparaben, propylparaben, and combinations thereof; from about 0.003 g to about 0.20 g of citric acid; from about 0.1 g to about 0.5 g of propylene glycol; and wherein the suspension of APAP without colorant has a pH of about 5 to about 6, and substantially free of a reducing sugar.

Another embodiment of the present invention includes a suspension of paracetamol without dye comprising, consisting, and / or consisting essentially, for every 100 mL of said suspension, in: from about 1 g to about 15 g of paracetamol; an active pharmaceutical agent selected from the group consisting of from about 0.1 g to about 1 g of pseudoephedrine HCl, from about 0.01 g to about 0.07 g of chlorpheniramine maleate, from about 0.05 g to about 0.5 g of dextromethorphan HBr, and mixtures thereof; from about 0.1 g to about 0.25 g of xanthan gum; from about 0.4 g to about 1 g of microcrystalline cellulose; from about 20 g to about 65 g of sorbitol solution; from about 1 g to about 20 g of glycerin; from about 0.01 g to about 1 g of flavor; from about 20 g to about 50 g of water; from about 0.001 g to about 0.10 g of an antimicrobial preservative selected from the group consisting of butylparaben, methylparaben, propylparaben, and combinations thereof; from about 0.003 g to about 0.20 g of citric acid; and from about 0.1 g to about 0.5 g of propylene glycol; wherein the suspension of paracetamol without colorant has a pH of about 5 to about 6, and substantially free of a reducing sugar. It is understood that both the foregoing general description and the following detailed description are exemplary but not restrictive of the invention.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "without colorant" is used herein as an adjective and means that a colorant per se is not added to the composition of matter at any point during its manufacture or packaging. As used herein, the term "reducing sugar" means a sugar that can be chemically reacted with a special copper reagent known as a Fehiings solution (alkaline solution), whereby the "reducing" sugar will reduce this copper to oxide solution. copper (cuprous oxide). Examples of reducing sugars include, without limitation, corn syrup, fructose and milk sugars. As used herein, the term "substantially free of a reducing sugar" means less than about 4 g / 100 mL of any reducing sugar. As used herein, the term "APAP" means paracetamol or N-acetyl-para-aminophenol, including without limitation the pharmaceutically acceptable salts, esters, or derivatives thereof. As used herein, the term "substantially water insoluble" refers to compositions that are insoluble, practically insoluble or slightly soluble in water, as defined in the 24th edition of the US Pharmacopoeia. UU These compositions require approximately 100 parts of solvent for a part of said composition, to complete the dissolution. The present invention provides a suspension system without dye particularly suitable for use in pharmaceutical suspensions. It is a discovery of the applicant that a stable and pourable non-colorant pharmaceutical suspension can be formed, having in suspension form an active agent substantially insoluble in water, for example APAP, and optionally additional active agents, at least one active agent substantially insoluble in water. additional, at least one active agent substantially soluble in water, or mixtures thereof, in suspended form, dissolved or both. In the following, the invention will be specifically described in terms of various modalities. One embodiment includes aqueous suspensions of the substantially water insoluble active agent APAP. APAP is a drug used for analgesic and antipyretic purposes both in over-the-counter preparations and in prescription medications. APAP is usually indicated for the temporary relief of minor aches and pains associated with the common cold, headache, dental pain, muscle pain, back pain, minor arthritis pain, for menstrual cramps pain and to reduce fever . In some embodiments, the suspension of the present invention will include APAP in suspended form, together with additional pharmaceutical active agents, which may be present in dissolved or suspended form. Reference will also be made in detail to other preferred embodiments of the compositions, processes and methods of the invention. Additional pharmaceutical active agents that are suitable include analgesic, anti-inflammatory, antiarthritic, anesthetic, antihistamine, antitussive, antibiotic, anti-infective, antiviral, anticoagulant, antidepressant, antidiabetic, antiemetic, antiflatulent, antifungal, antispasmodic, appetite suppressant, bronchodilator, cardiovascular agents. , agents of the central nervous system, central nervous system stimulants, decongestants, diuretics, expectorants, gastrointestinal agents, preparations for migraine, products for motion sickness, mucolytics, muscle relaxants, preparations for osteoporosis, polydimethylsiloxanes, respiratory agents, auxiliaries to sleep, agents for the urinary tract, and mixtures thereof. In one embodiment of the invention, the active agents can be selected from bisacodyl, famotidine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers and mixtures thereof. In another embodiment, the active agents can be selected from analgesics, anti-inflammatories and antipyretics: for example nonsteroidal anti-inflammatory drugs (NSAID's), which include propionic acid derivatives: for example ibuprofen, naproxen, ketoprofen and the like; Acetic acid derivatives: for example indomethacin, diclofenac, sulindac, tolmetin and the like; phenamic acid derivatives: for example mefenamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodilic acid derivatives: for example diflunisal, flufenisal and the like; and oxicams: for example piroxicam, sudoxicam, isoxicam, meloxicam, and the like. In a particularly preferred embodiment, the active agent is selected from an NSAID derived from propionic acid: for example, ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and salts, derivatives and combinations thereof pharmaceutically acceptable. In another embodiment of the invention, the active agent can be selected from APAP, acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celocoxib, and pharmaceutically acceptable salts, esters, isomers and mixtures thereof. . In another embodiment of the invention, the active agents can be selected from pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenamide, fexofenadine, loratadine, desloratadine, doxylamide, norastemizole, cetirizine, mixtures thereof, and salts, esters, isomers and mixtures thereof pharmaceutically acceptable. The agents or active ingredients are present in a "unit dose volume" of the aqueous suspension, in a therapeutically effective amount, which is an amount that produces the desired therapeutic response by oral administration, and can be determined easily by the expert in the field. In determining such amounts, the particular active agent to be administered must be considered, the bioavailability characteristics of the active agent, the dosing regimen, the age and weight of the patient, and other factors, as is known in the art. As used herein, "a unit dose volume" of the aqueous suspension is a convenient volume for dosing the product to a patient. The dosing instructions teach the patient to take amounts that are multiples of the unit dose volume, depending for example on the age or weight of the patient. Normally the unit dose volume of the suspension will contain a quantity of active agents that is therapeutically effective for the most petite patient. For example, suitable volumes of unit doses may include one teaspoon (approximately 5 ml), a spoonful (approximately 15 ml), a complete dropper, or a milliliter. In one embodiment, the aqueous pharmaceutical suspension composition according to the present invention includes from about 0.05% to about 40%, for example from about 0.05% to about 0.02%, or from about 1.6% to about 10%, or from about 15% to about 40% by weight per volume (w / v), of at least one active agent substantially insoluble in water. The amounts of active agent in this scale are generally acceptable to modify the taste. It is possible to include in the suspension more than 40% of an active agent substantially insoluble in water having the sufficiently masked flavor to be accepted by the consumer. Suspensions containing less than 0.05% of active pharmaceutical agents are also possible. In an embodiment wherein the first active agent is APAP, the amount of active agent in the suspension is from about 80 mg to about 160 mg per 1.6 ml, or from about 5% to about 10% w / v. In another embodiment wherein the first active agent is APAP, the amount of active agent in the suspension is from about 80 mg to about 160 mg per teaspoon, or from about 1.6 g to about 3.2 g per 100 mL, or about 1% a approximately 4% p / v. The present inventor has found that the unique combination of APAP having sorbitol and sucrose, at a pH of about 5.1 to 5.9, advantageously produces APAP suspensions that are stable in storage and dispersed homogeneously. The pharmaceutical suspension of the present invention may contain at least one additional pharmaceutical agent. Said additional pharmaceutical active agent can be an antihistamine, antitussive, guafenesin, and a sympathomimetic. Examples of antihistamines include those selected from the group consisting of chlorpheniramine maleate, terfenadine, astemizole, diphenhydramine hydrochloride, and mixtures thereof. Examples of antitussives include those selected from the group which consists of dextromethorphan HBr, diphenhydramine hydrochloride, and mixtures thereof. Examples of sympathomimetics include those selected from the group consisting of pseudoephedrine hydrochloride, phenylpropanolamine, and mixtures thereof. The suspension of the present invention may also include a taste masking composition for masking the bitter taste of the active agents of the composition, particularly suspended paracetamol. Generally, the taste masking composition contains at least one sweetening agent and at least one flavoring agent. The flavoring agents added to the mixture must be of the type and quantity desired for the particular suspension to cover the preferences dictated by the consumer to whom said suspension is intended, for example pediatric or adult. Suitable sweetening agents are non-reducing sugars, alcohols, polyhydric and high intensity sweeteners. Examples of suitable non-reducing sugars include, without limitation, the heterodisaccharides sucrose, lactose, raffinose, stachyose; the non-reducing homodisaccharide trehalose; and the non-reducing homooligosaccharides cyclomaltohexa (... deca) osa (also known as Schardinger dextrins). The amount of sugar sweetener used in the suspension will vary depending on the degree of sweetness desired for the suspension particular. Generally, the amount of sugar sweetener will be in the range of 0 g to about 110 g per 100 mL of the suspension. The amount of sugar sweetener may also be in the range of about 40 g to about 100 g per 100 mL of the suspension. Instead of, or in addition to, sugar sweeteners, water-soluble high-intensity sweeteners may also be employed. Examples of suitable high intensity sweeteners include, without limitation, sucralose, aspartame, saccharin, acesulfame, cyclamate, and pharmaceutically acceptable salts and combinations thereof. The amount of high intensity sweetener used in the suspension will vary depending on the degree of sweetness desired for the particular suspension. Generally, the amount of high intensity sweetener used in the suspension can range from 0 g to about 5 g per 100 mL of suspension. In embodiments employing a high intensity sweetener such as sucralose, aspartame, acesulfame, saccharin and pharmaceutically acceptable salts thereof, the amount of high intensity sweetener is from 0 g to about 1 g per 100 mL of suspension; a useful amount is from about 0 g to about 0.5 g per 100 mL of suspension. The pharmaceutical suspension of the present invention is substantially free of reducing sugars. The monosaccharide reducing sugars which are unsuitable for use in the present invention include, without limitation, glucose, fructose, galactose, ribose, mannose, sorbose, arabinose and xylose. Reducing oligosaccharides which are unsuitable for use in the present invention include, without limitation, cellobiose, isomaltose, maltose, gentibiose, laminaribiose; maltotriose, maltotetrose, maltopentose, maltohexose; the reducing sugars heterodisaccharides include, without limitation, lactose, lactulose, maltulose, melibiose. The reducing sugars are hydroxyaldehydes and open-chain hydroxyketones, and are easily oxidized to form acids. The basic amino groups of the proteins, peptides and amino acids are easily bound to the carbonyl groups of the acyclic (reducing) sugars by means of a condensation reaction. The Maillard reaction, a well-known reaction that results in the formation of a brown color, proceeds by enolization of the resulting glycosylamines. A second type of sugar decomposition reaction that also produces a brown color, originates from the enolization of hydroxyaldehydes and hydroxyketones at a pH of less than 4 and at an elevated temperature, followed by dehydration, to form furfurals (2-furaldehydes). This type of reaction is sometimes referred to as "caramelization". Examples of suitable polyhydric alcohols for use as sweeteners in the present invention include, without limitation, sorbitol, mannitol, xylitol, erythritol, maltitol, and the like, and combinations thereof. The amount of polyhydric alcohol sweetener used in the suspension will vary depending on the degree of sweetness desired for the particular suspension. Generally the amount of polyhydric alcohol sweetener it will be on the scale from about 0 g to about 90 g per 100 mL of the suspension. . - Suitable flavoring agents include natural and / or artificial flavors such as mints (ie, peppermint, etc.), menthol, cinnamon, vanilla, artificial vanilla, chocolate, artificial chocolate, natural and artificial fruit flavors (e.g. cherry, grape, orange, strawberry, etc.), and combinations of two or more thereof. Frequently the flavoring agents are complex mixtures of chemical compounds, dissolved or dispersed in an inert medium such as propylene glycol. Generally these solutions or dispersions are provided as a minor component of the suspension, in effective amounts to give a pleasant taste to the suspension. However, generally, flavoring agents will be present in the suspension in amounts on the scale at about 0 g to about 5 g per 100 mL of the suspension. In some embodiments, optimum taste masking of the solid active agent in the suspension can be obtained by limiting the amount of water available in the suspension to solubilize the active agents. The minimum amount of water should provide the suspension with a sufficient aqueous base to impart the desired degree of hydration of the suspending agents. In some of these embodiments, in order to mask the taste of the bitter pharmaceutical agents it is required that the total amount of water contained in the suspension be in the range of about 25 g to about 60 g, preferably of about 30 g to about 55 g per 100 mL of suspension. The pH of the suspension should be optimized to minimize the solubility and maximize the chemical stability of any active agent with unpleasant taste and susceptible to hydrolysis, for example APAP. Ideally, the pH of the suspension should be as close as possible to 2 pH units above the pKa of a basic active agent, and as close as possible to 2 pH units below the pKa of an acidic active agent. In some embodiments employing APAP as the active agent, the pH of the suspension should be in the range of about 5 to about 6, for example about 5.1 to approximately 5.9. The suspension can be made buffers by using pH adjusters to maintain the pH of the suspension at the desired pH scale. Suitable pH adjusting agents may be present in the suspension in amounts sufficient to provide the desired degree of buffering of pH. The pH adjusting agents will normally be present in the range from about 0 g to about 1 g per 100 mL of the pharmaceutical suspension without dye. The pH adjusting agent for a modality that has as an active agent, and includes a suspension system having alkaline polymers such as sodium carboxymethylcellulose, can be selected from weak organic acids, such as citric acid, malic acid, glutamic acid and the like, which have acceptable flavor characteristics for use in flavored oral suspensions. masked. You can add citric acid to the suspension to stabilize its pH from about 4.5 to about 6.5, for example from about 5.1 to about 5.9. It is useful to add citric acid to this pH scale (ie, from about 4.5 to about 6.5), since it will increase the stability of the pharmaceutical suspension without dye. A useful pH for the suspension when the active pharmaceutical agent used is the APAP, is between about 5.1 and about 5.9, since the APAP will suffer the least degradation in suspension. Antimicrobial preservatives are selected according to their activity within this pH range. Useful preservatives in pharmaceutical suspensions without dye include, without limitation, sodium benzoate, potassium sorbate, salts of edetate (also known as salts of ethylenediaminetetraacetic acid, or EDTA, such as disodium edetate) and parabens (such as esters the methyl-, ethyl-, propyl- and butyl-p-hydroxybenzoic acids). The aforementioned conservatives are exemplary, but each conservator must be evaluated on an empirical basis, in each formulation, to ensure the compatibility and effectiveness of the conservator. Methods for evaluating the efficacy of preservatives in pharmaceutical formulations are known to the person skilled in the art. The para-aminobenzoic acid derivatives, for example butylparaben, methylparaben and propylparaben, are particularly useful preservative ingredients to be added to a pharmaceutical suspension without APAP-containing dye, due to their superior activity in the particularly preferred pH scale of about 5 to about 6. In a particularly useful embodiment, the pharmaceutical suspension without dye of the present invention is substantially free of benzoic acid and its derivatives, since these have a suboptimal activity on the preferred pH scale. The preservatives will generally be present in amounts of up to 1 g per 100 mL of the suspension. Preferably, preservatives will be present in amounts ranging from about 0.01 g to about 0.5 g per 100 mL of the suspension. For pharmaceutical suspensions without colorant containing APAP it is useful that propylparaben preservative is present in the range of about 0.01 g to about 0.1 g per 100 mL of the pharmaceutical suspension without colorant and butylparaben preservative is present in the range of about 0.01 g approximately 0.1 g per 100 mL of the pharmaceutical suspension without dye. It is more useful that propylparaben be present in a concentration of 0.045 g per 100 mL of the pharmaceutical suspension without dye, and butylparaben in a concentration of approximately 0.045 g per 100 mL of the pharmaceutical suspension without dye. The pharmaceutical suspension without dye of the present invention is substantially free of coloring agents, such as tinctures or lacquers. However, the pharmaceutical suspension without dye of the present invention can optionally incorporate some pigments as opacifiers, for example titanium dioxide and the like.

The suspensions may also contain one or more of the following additives: antifoaming agents, surfactants; electrolytes (currently monovalent cations are preferred); and sequestering agents. In some optional embodiments, the pharmaceutical suspension without dye of the invention can employ a surfactant to be used as a wetting agent, to help disperse some hydrophobic active agents. In some other embodiments, the suspension of the invention may be substantially free of surfactant. In embodiments employing surfactant, one useful surfactant is a sorbitan oleate ester, particularly polyoxyethylene sorbitan monooleate also known as polysorbate 80. The suspensions of the present invention can employ suspending systems as known in the art, including, without limitation, at least one thickener component. The thickener component typically includes one or more thickening agents that can be selected from hydrophilic polymers, that is, water soluble, such as hydrocolloids, swellable or gellable polymers, and the like. In one embodiment, the thickener component combines the attributes of a structuring agent and a swelling agent. In another preferred embodiment, the thickener component combines the attributes of at least two structuring agents, for example a primary structuring agent and a secondary structuring agent.

When a structuring agent is introduced into an appropriate aqueous medium, it forms an ordered structure that is believed to be stabilized by hydrogen bonds and molecular entanglement. Hydrocolloids are a particularly good type of structuring agent. Hydrocolloids are dispersions of particles around which water molecules and solvated ions form a structure similar to a cover, fluid absorption occurs mainly by swelling and enlargement of the structure. Examples of suitable hydrocolloids include, without limitation, alginates, agar, guar gum, locust bean gum, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, galane, maltodextrin, galactomannan, pustulan, laminarin, scleroglucan, gum arabic, inulin. , karaya, welan, ramsan, zuglan, methylan, chitin, cyclodextrin, chitosan, cellulosic polymers such as microcrystalline cellulose, carboxymethylcellulose, and derivatives and combinations thereof. In some embodiments of the present invention, useful structuring agents can be selected from the hydrocolloids xanthan gum, microcrystalline cellulose, carboxymethyl cellulose and derivatives, coprecipitates and combinations thereof. In a particularly useful embodiment, the thickener component includes xanthan gum as the primary structuring agent and a co-processed combination of microcrystalline cellulose and carboxymethylcellulose (for example that commercially available from FMC as Avicel-RC 591), as a secondary structuring agent.

Xanthan gum is a natural carbohydrate of high molecular weight, specifically a polysaccharide. The xanthan gum suitable for use in the present invention is a high molecular weight polysaccharide produced by Xanthomonas campestris. The techniques and strains for producing this polysaccharide are described in US Pat. UU Nos. 4,752,580 and 3,485,719 (the descriptions of which are incorporated herein by reference). The xanthan gum used in the present invention should have a viscosity in a 1% salt solution, from about 1000 cP to about 1700 cP (mPa-s). The viscosity of the 1% solution should be measured at 25 ° C with a Brookfield Synchro-Lectric model LV viscometer at 60 rpm, spindle no. 3. Xanthan gum is available from several commercial suppliers, such as RT Vanderbilt Company and CP Kelco. Examples of suitable xanthan gums are Keltrol, Keltrol F, Keltrol T, Keltrol TF, Xantural 180 and Vanzan NF-ST. In a useful embodiment, the secondary structuring agent used in the present invention is a dry coprecipitated microcrystal of cellulose and sodium carboxymethylcellulose. Sodium carboxymethylcellulose is commonly used as a coprecipitate in microcrystalline cellulose. It is particularly useful if the sodium carboxymethylcellulose is included in the range from about 8% to about 19% of the total weight of the co-precipitated microcrystal of cellulose and sodium carboxymethylcellulose. Microcrystalline cellulose products are useful which are in the range of about 8% to about 14% by weight of 4 Sodium carboximethylcelulose. These mixtures, as described above, are commercially available from a variety of suppliers including FMC, under the trademark Avicel® CL-611, Avicel® RC-581 and Avicel® RC-591. The thickener component can optionally comprise a swelling agent, which when expanded to an appropriate aqueous medium expands and can interact with the structuring agent. Pregelatinized starch is a particularly good swelling agent. The pregelatinized starch, also known as "instant" starch, is precooked, so that it swells and begins to thicken instantly when added to cold water. A particularly suitable pregelatinized starch is prepared from food-grade, modified, stabilized and waxy corn starch, and is commercially available from the National Starch Company as instant starch Ultrasperse M. In some embodiments, an optional auxiliary suspending agent is used in the present invention. The auxiliary suspending agent can be selected from the group consisting of hydroxyethylcellulose and a pharmaceutically acceptable salt of carboxymethylcellulose. Suitable pharmaceutically acceptable salts of carboxymethylcellulose include the sodium and calcium salts of a cellulose polycarboxymethyl ether, commercially available as sodium carboxymethylcellulose USP, and calcium carboxymethylcellulose NF. Sodium carboxymethylcellulose USP contains from about 6.5% to about 7.5% by weight of sodium in dry base, and is commercially available from Aqualon Co, under the 5 Aqualon product designation. Hydroxyethylcellulose is a partially substituted cellulose poly (hydroxyethyl) ether. Hydroxycellulose NF is available from Aqualon Co under the designation Natrosol product. The present invention also provides a process for preparing the pharmaceutical composition in aqueous suspension. A useful method includes the following sequential steps: (a) adding from about 35% to about 40% by weight of water to achieve an adequate volume to mix; (b) dispersing from about 0.5% to about 1.0% microcrystalline cellulose and carboxymethylcellulose (coprocessed), and from about 0.1% to 0.2% xanthan gum, and mixing until hydrated; (c) adding from about 10% to about 50% of sweet polyhydric alcohol, preferably sorbitol, by weight per volume of the total suspension, followed by about 5% to about 20% glycerin. (d) in some embodiments, optionally add to the dispersion of step (c) from about 10% to about 50% sugar, preferably sucrose, by weight per volume of the total suspension, and stir until the ingredients are uniformly dispersed in mix; (e) add to the mixture of step (d) sufficient anhydrous citric acid powder to lower the pH of the solution to a value of between about 4.5 and about 6.5, until the ingredients are dispersed evenly throughout the mixture; or in other embodiments, anhydrous sodium citrate powder is added to adjust the pH; (f) adding a mixture of from about 0.03% to about 0.06% propylparaben and from about 0.03% to about 0.06% butylparaben dissolved in about 0.1% to about 1.0% propylene glycol; (g) adding the first active agent, for example from about 3% to about 12% APAP, followed by the flavoring system from about 0.05% to about 0.15%, and suitable high intensity sweetener, for example about 0.1% a approximately 0.2% sucralose; and (h) adding to the mixture of step (g) sufficient water and stirring, to produce a pharmaceutical suspension without dye of 100% of the desired volume. In useful embodiments of the process, an effective amount of preservative, such as for example propylparaben and butylparaben, is added to the mixture in step (f), and the suspension of step (h) is subjected to a deaeration step, in such a manner that the volume of the suspension is adjusted to 100% by adding water after said deaeration. The flavoring ingredients added to the mixture in step (g) may be of the type and amount desired so that the particular suspension meets the preferences dictated by the consumer to whom said suspension is directed, for example, pediatric or adult. In the following examples a more detailed example of a useful method of the present invention is given. The viscosity of the suspension is measured using a viscometer Brookfield LV, equipped with No. 31 spindle. A sample from a closed bottle was placed in the sample chamber and equilibrated in a 25 ° C water bath. After equilibration, the sample was stirred at 1.5 rpm and the viscosity was read after 2 min. The useful viscosity of the suspension of the present invention is from about 1500 centipoise to about 7000 centipoise, for example not less than 1800 centipoise, or not less than 2300 centipoise, measured according to the above method.

EXAMPLES The invention will now be described by means of examples.

These examples are not intended to be limiting of the scope of the present invention, but read together with the above detailed and general description, they provide a better understanding of the present invention and an outline of the preferred process for preparing the compositions of the invention.

EXAMPLE 1 Suspension of APAP without coloring Operating Instructions 1.- To a tared vessel, equipped with a high shear vacuum mixer, add approximately 35% to approximately 40% by weight of purified water to obtain an adequate volume to mix. 2.- Disperse from approximately 0.5% to approximately 1. 0% microcrystalline cellulose and carboxymethylcellulose (coprocessed), and from about 0.1% to about 0.2% xanthan gum and stir until hydrated. 3.- Add the sorbitol solution, followed by glycerin and stir. 4.- Add the sucrose and stir until it dissolves. 5.- Add anhydrous citric acid powder, followed by propylparaben and butylparaben previously dissolved in propylene glycol, and stir until dissolved. 6.- Disperse the APAP, followed by sucralose and the flavoring system, and stir. 7.- Bring the suspension to a final volume with purified water, and stir in vacuum to deaerate. The above produces a batch size of approximately 7570 liters or 2000 gallons of paracetamol suspension without dye (100 mg / 5 ml), with a pH of 5.5.

EXAMPLE 2 Drops of suspension of APAP without coloring Operating Instructions 1.- To a tared vessel, equipped with a high shear vacuum mixer, add approximately 35% by weight of purified water and approximately 24% by weight of sorbitol solution to obtain an adequate volume to mix. 2.- Disperse from approximately 0.5% to approximately 1.0% of microcrystalline cellulose and carboxymethylcellulose (coprocessed), and from about 0.1% to about 0.2% xanthan gum and stir until moisturized. 3.- Add the remaining sorbitol solution, followed by glycerin, and stir. 4.- Add anhydrous citric acid powder, followed by propylparaben and butylparaben previously dissolved in propylene glycol, and stir until dissolved. 5.- Add the APAP, followed by sucralose and the flavoring system, and stir to disperse. 6.- Bring the suspension to a final volume with purified water, and stir in vacuum to deaerate. This produces a batch size of approximately 3785 liters of paracetamol drops in suspension (80 mg /0.8 ml), without dye, with a pH of 5.5.

EXAMPLE 3 Dose form in suspension drops of APAP, dextromethorphan HBr and pseudoephedrine HCl, without dye The procedure of Example 2 is carried out, except that dextromethorphan hydrobromide is added and stirred to dissolve it between the hydration of the microcrystalline cellulose and the carboxymethylcellulose. (co-processed) and xanthan gum. Just before the addition of paracetamol, pseudoephedrine hydrochloride is added and stirred Dissolve it Anhydrous sodium citrate powder is added instead of anhydrous citric acid to adjust the pH.

EXAMPLE 4 Suspension dose form of APAP, dextromethorphan HBr, pseudoephedrine HCl and chlorpheniramine maleate, without colorant The procedure of Example 1 is carried out, except that dextromethorphan hydrobromide is added and stirred to dissolve it between the hydration of microcrystalline cellulose and carboxymethylcellulose (coprocessed) and xanthan gum. Just before the addition of paracetamol, the chlorpheniramine maleate and the pseudoephedrine hydrochloride are added and stirred to dissolve them.

EXAMPLE 5 Comparison of suspensions containing HFCS and suspensions substantially free of reducing sugars Suspension drops of paracetamol, dextromethorphan HBr and pseudoephedrine free HCl dye The procedure of example 3 is carried out, except that in suspensions containing the different amounts of 55% high-fructose corn syrup, a portion of the 70% USP sorbitol solution is removed to allow the addition. The 4 samples were packed and placed under stress conditions of 40 ° C and 50 ° C for several weeks. After observing the samples submitted to the stress conditions in the various periods, for example 1 week, 2 weeks, etc., it was observed that in the samples containing 55% high-fructose corn syrup, the degree of discoloration developed was increased. The following is the discoloration of droplets in suspension of paracetamol, dextromethorphan HBr and pseudoephedrine HCl without dye in samples subjected to temperature stress.

Comparison of suspensions containing HFCS and suspensions substantially free of reducing sugars * Color observations: NC: no change. 1. Very light change, remarkable for a trained analyst. 2. Definitive change, notable for a trained analyst. 3: Change barely noticeable for a consumer. 4: Definitive change, remarkable for a consumer. 5: Extreme change. Suspensions containing reducing sugar in an amount as low as 5% w / v show a more noticeable discoloration than the preferred suspension without reducing sugar. The scope of the present invention is not limited by the description, examples and suggested uses herein; Modifications can be made without departing from the spirit of the invention. For example, additional drugs may be added to the aqueous suspension to provide a combination medication. In addition, the pharmaceutical suspension of the invention can be used for non-medicinal ingredients, including nutrients such as vitamins and minerals. The application of the compositions and method of the present invention for medical and pharmaceutical uses can be done by any clinical, medical and pharmaceutical method or technique, such as those currently known or known prospectively to the person skilled in the art. Thus, it is considered that the present invention covers the modifications and variations of this invention, provided they are within the scope of the appended claims and their equivalents.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A pharmaceutical suspension without dye comprising: (a) a therapeutically effective amount of a first active agent consisting essentially of a first active agent substantially insoluble in water; (b) an effective amount of a non-reducing sweetener; (c) an effective amount of water; and (d) an effective amount of a suspension system; wherein the pharmaceutical suspension without dye has a pH of about 5 to about 6, and is substantially free of a reducing sugar. 2. The pharmaceutical suspension without dye according to claim 1, further characterized in that the non-reducing sweetener is selected from the group consisting of non-reducing sugars, polyhydric alcohols, high intensity sweeteners, and combinations thereof. 3. The pharmaceutical suspension without dye according to claim 2, further characterized in that the non-reducing sweetener comprises a combination of sucrose and sorbitol. 4. The pharmaceutical suspension without dye according to claim 1, further characterized in that the suspension system consists essentially of about 0.1 g to about 0.25 g of xanthan gum per 100 mL of the suspension, and about 0. 4 g to about 1 g of microcrystalline cellulose per 100 mL of the suspension. 5. The pharmaceutical suspension without dye according to claim 1, further characterized in that it comprises a therapeutically effective amount of a second active agent, selected from the group consisting of a second active agent substantially insoluble in water, a water soluble active agent , or mixtures thereof. 6. The pharmaceutical suspension without dye according to claim 5, further characterized in that the second active agent is selected from the group consisting of an antitussive, an expectorant, an antihistamine, a sympathomimetic, and mixtures thereof. 7. The pharmaceutical suspension without dye according to claim 6, further characterized in that the second active agent (at least one) is an antihistamine selected from the group consisting of chlorpheniramine maleate, terfenadine, astemizole, diphenhydramine hydrochloride, and mixtures thereof. 8. The pharmaceutical suspension without dye according to claim 6, further characterized in that the second active agent is an antitussive selected from the group consisting of dextromethorphan HBr, diphenhydramine hydrochloride, and mixtures thereof. 9- The pharmaceutical suspension without dye according to claim 6, further characterized in that the second active agent is guaifenesin. 10. - The pharmaceutical suspension without dye according to claim 6, further characterized in that the second active agent is a sympathomimetic selected from the group consisting of pseudoephedrine hydrochloride, phenylpropanolamine, and mixtures thereof. 11. The pharmaceutical suspension without dye according to claim 6, further characterized in that the second active agent comprises pseudoephedrine hydrochloride and chlorpheniramine maleate. 12. The pharmaceutical suspension without dye according to claim 9, further characterized in that the second active agent also comprises dextromethorphan hydrobromide. 13. The pharmaceutical suspension without dye according to claim 1, further characterized in that the sweetening agent is selected from the group consisting of xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially starch solids hydrolyzed, solids of partially hydrolyzed corn syrup, sorbitol, xylitol, mannitol, glycerin, aspartame, sucralose, cyclamates, saccharin and mixtures thereof. 14. The pharmaceutical suspension without dye according to claim 1, further characterized in that it comprises from about 25 grams to about 60 grams of water per 100 mL of the suspension. 15.- The pharmaceutical suspension without colorant according to claim 1, further characterized in that it has a viscosity of approximately 1500 centipoises to approximately 7000 centipoises. 16. The pharmaceutical suspension without dye according to claim 5, further characterized in that the second active agent is substantially dissolved. 17. An APAP suspension without dye comprising: (a) a therapeutically effective amount of APAP; (b) an effective amount of a non-reducing sweetener; (c) an effective amount of water; and (d) an effective amount of a suspension system; wherein the pharmaceutical suspension without dye has a pH of about 5 to about 6, and is substantially free of a reducing sugar. 18. The suspension of APAP without colorant according to claim 17, further characterized in that the non-reducing sweetener is selected from the group consisting of non-reducing sugars, polyhydric alcohols, high intensity sweeteners, and combinations thereof. 19. The suspension of APAP without dye according to claim 18, further characterized in that the non-reducing sweetener comprises a combination of sucrose and sorbitol. 20. The suspension of APAP without dye according to claim 17, further characterized in that the suspension system consists essentially of about 0.1 g to about 0.25 g of xanthan gum per 100 ml of the suspension, and about 0.4 g to about 1 g. g of microcrystalline cellulose per 100 mL of the suspension. 21. - The suspension of APAP without dye according to claim 17, further characterized in that it comprises a therapeutically effective amount of a second active agent, selected from the group consisting of a second active agent substantially insoluble in water, a water-soluble active agent, or mixtures thereof. 22. The suspension of APAP without dye according to claim 21, further characterized in that the second active agent is selected from the group consisting of an antitussive, an expectorant, an antihistamine, a sympathomimetic, and mixtures thereof. 23. The suspension of APAP without dye according to claim 21, further characterized in that the second active agent is an antihistamine selected from the group consisting of chlorpheniramine maleate, terfenadine, astemizole, diphenhydramine hydrochloride, and mixtures thereof. 24. The suspension of APAP without dye according to claim 21, further characterized in that the second active agent is an antitussive selected from the group consisting of dextromethorphan HBr, diphenhydramine hydrochloride, and mixtures thereof. 25- The APAP suspension without dye according to claim 21, further characterized in that the second active agent is guaifenesin. 26.- The suspension of APAP without colorant according to claim 21, further characterized in that the second active agent is a sympathomimetic selected from the group consisting of pseudoephedrine hydrochloride, phenylpropanolamine, and mixtures thereof. 27. The suspension of APAP without dye according to claim 21, further characterized in that the second active agent comprises pseudoephedrine hydrochloride and chlorpheniramine maleate. 28. The suspension of APAP without dye according to claim 27, further characterized in that the second active agent also comprises dextromethorphan hydrobromide. 29. The suspension of APAP without colorant according to claim 17, further characterized in that it comprises a taste masking composition comprising at least one sweetening agent and at least one flavoring agent. 30. The suspension of APAP without dye according to claim 29, further characterized in that the sweetening agent is selected from the group consisting of xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, starch solids. partially hydrolyzed, partially hydrolyzed corn syrup solids, sorbitol, xylitol, mannitol, glycerin, aspartame, sucralose, cyclamates, saccharin and mixtures thereof. 31.- The suspension of APAP without colorant according to claim 17, further characterized in that it comprises from approximately 25 grams to approximately 60 grams of water per 100 mL of the suspension. 32. - The suspension of APAP without colorant according to claim 17, further characterized in that it has a viscosity of about 1500 centipoise to about 7000 centipoise. 33.- The suspension of APAP without dye according to claim 21, further characterized in that the second active agent is substantially dissolved. 34.- A suspension of APAP without dye comprising, for each 100 mL of said suspension: from approximately 1 g to approximately 15 g of APAP; from about 0.1 g to about 0.25 g of xanthan gum; from about 0.4 g to about 1 g of microcrystalline cellulose; from about 20 g to about 65 g of sorbitol solution; from about 1 g to about 20 g of glycerin; from about 0.01 g to about 1 g of flavor; from about 20 g to about 50 g of water; from about 0.001 g to about 0.10 g of an antimicrobial preservative selected from the group consisting of butylparaben, methylparaben, propylparaben, and combinations thereof; from about 0.003 g to about 0.20 g of citric acid; from about 0.1 g to about 0.5 g of propylene glycol; and wherein the suspension of APAP without colorant has a pH of about 5 to about 6, and substantially free of a reducing sugar. 35.- A suspension of paracetamol without dye that comprises, for every 100 mL of said suspension: from about 1 g to about 15 g of paracetamol; an active pharmaceutical agent selected from the group consisting of from about 0.1 g to about 1 g of pseudoephedrine HCl, from about 0.01 g to about 0.07 g of chlorpheniramine maleate, from about 0.05 g to about 0.5 g of dextromethorphan HBr, and mixtures thereof; from about 0.1 g to about 0.25 g of xanthan gum; from about 0.4 g to about 1 g of microcrystalline cellulose; from about 20 g to about 65 g of sorbitol solution; from about 1 g to about 20 g of glycerin; from about 0.01 g to about 1 g of flavor; from about 20 g to about 50 g of water; from about 0.001 g to about 0.10 g of an antimicrobial preservative selected from the group consisting of butylparaben, methylparaben, propylparaben, and combinations thereof; from about 0.003 g to about 0.20 g of citric acid; and from about 0.1 g to about 0.5 g of propylene glycol; wherein the suspension of paracetamol without colorant has a pH of about 5 to about 6, and substantially free of a reducing sugar.